Amyloid beta-protein (A-beta) is the major protein of cerebrovascular and plaque amyloid in brains of normal aged individuals and patients with Alzheimer's disease (AD). A-beta exists as both soluble and fibrillar form. Age related deposition of fibrillary form of Ap in the brain is a major cause of dementia in Alzheimer's disease (AD). The mechanisms responsible for aggregation and fibrillization of A- beta are poorly understood. Several proteins such as apolipoprotein E, apolipoprotein J and transthyretin have been shown to bind to A- beta. The cations such as Zn2+, Al3+ and Ca2+ have been shown to promote fibrillization of synthetic A-beta. The interaction of Ca2+ with A-beta seems to be complex as we observed that Ca2+ can also disaggregate and dissolve the preformed A-beta fibrils. Our preliminary results indicate that polyphosphoinositides, a constituent of amyloid core, promote the fibrillization of soluble A- beta in the order of phosphatidylinositol (PI) 4,3-bisphosphate (PIP2) > PI 4-P >PI. Several other factors, yet unidentified, may be involved in the promotion or disaggregation of A-beta fibrils. We plan to study the effect of other inorganic cations (Mg2+, Al3+, Zn2+) and polyvalent organic cations (spermine, spermidine and putrescine) on the preformed A-beta fibrils. Attempt will also be made to defibrillize the fibrils isolated from amyloid core by treating it with most potent cation identified by the above studies. We will also study the effect of polyarginine containing proteins on the aggregation of Ap since apolipoprotein E that binds to A43 is a arginine rich polycationic protein. The organic anionic lipids (sulfatide, ganglioside) and neutral lipid (cerebroside) which are mainly present in the brain will also be studied for their effects on the aggregation of soluble A-beta, and compared with that of other lipid molecules such as phosphatidylserine, cholesterol, phosphatidylcholine and phosphatidylethanolamine that are present in other tissues also. This pilot study will help in identifying various cations and lipids that can modulate the fibrillization of A-beta and disaggregate the A-beta fibrils.